An o-bromophenyl lithium can be synthesized by reacting ortho-dibromobenzene in a specific mixed solvent at −110° C. via a metal-halogen exchange reaction. However, it is known that the thus-lithiated o-bromophenyl lithium is so unstable that if a temperature is elevated to −90° C., the lithiated compound is easily decomposed to form benzyne which resultantly forms a series of by-products (Chen, L. S.; Chen, G. J.; Tamborski, C. J. Organometal. Chem., 1980, 193, 283-292). Therefore, it has been thought that from the necessity of severe temperature control to −90° C. or lower, it is difficult to cause reaction of the above-described lithiated compound with an electrophilic compound at a higher temperature than −90° C.
In this aspect, the present inventors proposed a method for obtaining a bromobenzene, at −78° C., by using a microreactor, to obtain a mono-lithiated product of 1,2-dibromobenzene, and then reacting the mono-lithiated product with methanol, to cause protonation (Hirotsugu Usutani, Toshiki Nokami, Hideho Okamoto, Jun-ichi Yoshida, the 86th Annual Convention (Spring Session) of Nippon Kagaku Kai (the Chemical Society of Japan), Preprints, 3H2-45 (2006), published on Mar. 13, 2006; the disclosure of which is herein incorporated by reference).
Further, the present inventors proposed a method in which a halogen compound is allowed to react with a lithium agent using a microreactor to obtain a mono-lithiated product of the halogen compound, and then the thus-obtained mono-lithiated product is allowed to react with an electrophilic compound (JP-A-2006-241065 (“JP-A” means unexamined published Japanese patent application)). However, this publication discloses a reaction of only one halogen atom of the halogen compound, but the publication is silent on that an o-dihaloaromatic compound having two halogen atoms adjacent to each other on the aromatic ring be converted to the corresponding o-disubstituted aromatic compound. Besides, the method described in this patent publication is characterized in that mono-lithiation can be performed at the reaction temperature of from −10 to 40° C. that is extremely higher than a conventional temperature, but there is no description that an o-dihaloaromatic compound having two halogen atoms adjacent to each other on the aromatic ring be converted to the corresponding o-disubstituted aromatic compound.
Accordingly, it has been eagerly desired the development of a method capable of producing an o-disubstituted aromatic compound, efficiently with a high yield, by electrophilic substitution reaction of each of two halogen atoms of an o-dihaloaromatic compound.